Disorders affecting the spinal cord (myelopathies) can cause severe disability. Despite diagnostic advances, approximately 12-18% of myelopathy cases continue to elude an etiological diagnosis, hampering effective treatment.

We retrospectively screened 2,587 patients enrolled in a suspected neuroinflammatory disease research study for a diagnosis of idiopathic myelopathy (IM). We performed programmable phage display to discover novel autoantibodies in the cerebrospinal fluid (CSF) of these patients. Orthogonal immunoassays were used to confirm a candidate autoantibody.

200 patients (8%) presented with myelopathy. 184 patients (92%) eventually received etiological diagnoses, leaving 16 patients (8%) with IM. 16 additional patients with IM were enrolled after the initial screen, comprising a total of 32 patients in the discovery cohort. Autoantibodies targeting the transcobalamin receptor (CD320) were identified in 18 out of 32 patients (56%). Bioactive vitamin B12 concentration was decreased in the CSF of anti-CD320 positive patients (P = 0.0273), indicative of autoimmune B12 central deficiency (ABCD). Compared to negative IM cases, positive IM cases demonstrated a higher frequency of dorsolateral cord abnormalities on magnetic resonance imaging (MRI) (61% vs 7%, P = 0.003) and normal CSF profile (83% vs 50%, P = 0.044). In two independent validation cohorts comprising 94 and 25 patients with IM, anti-CD320 was detected in 43 (46%) and 12 (48%) patients, respectively. Four patients received B12 supplementation and clinically improved.

ABCD underlies a substantial proportion of IM. B12 supplementation may be an effective treatment, but prospective studies will be necessary to assess causality and therapeutic efficacy.